This project will use gene reporters to a large spectrum of known eukaryotic genes to define the transcriptional and translational response of cells to treatment with drugs. The identification of genes whose expression changes in response to drug treatment will reveal nearly every aspect of cellular metabolism affected by a drug. Response profiles of mutant cells lacking the presumed target of the drug will reveal how a perfect drug for that target would impact cell. Comparisons of response profiles caused by drug treatment to profiles of mutant cells will reveal how close to perfect specificity the candidate drug is. This work will reveal many of the potential side effects of a drug along with potential synergies that could be achieved by combination therapies. The proposed research will provide unprecedented insight into mechanism and specificity of drugs and drug candidates, lead to a radically new approach to the identification of new lead compounds for human therapeutics, and dramatically extent the number of therapeutic targets. Unlike conventional drug screening in which large numbers of compounds are tested against individual targets, the technology behind the proposed research should identify the intracellular targets of chemical compounds regardless of what those targets are. PROPOSED COMMERCIAL APPLICATION: The methodology being developed with this research will have significant commercial applications in the pharmaceutical industry. Specifically, it is designed to reinvent the process ods to discover and develop new leads for human therapeutics. If successful, this technology could greatly reduce the discovery and development phase of drug development, and hence reduce the costs associated with this lengthy process.